The present invention relates, inter alia, to a smokeless tobacco product an extrudable tobacco composition, a method for manufacturing a smokeless tobacco product and a method for delivering nicotine contained in tobacco to a user.
American consumption of smokeless tobacco is growing while cigarette smoking is declining. Awareness of the potential health risks of smoking, the potential risks of second hand smoke to third parties, and the increasing existence of cigarette smoking bans are all factors that are helping to shift tobacco consumption from cigarettes to smokeless tobacco. U.S. sales of moist snuff increased 10% in 2006 after several years of 6% growth while cigarette consumption decline. Another potentially contributing factor to this shift is the increasingly held view in the public health community that smokeless tobacco may be much less harmful to the health of the user than is cigarette smoking.
Smokers want alternatives to cigarette smoking. UST Inc., a holding company for U.S. Smokeless Tobacco Company, estimates that over half of US smokers are seeking smoking alternatives. Despite this fact, US smokers are generally reluctant to try smokeless tobacco products. Traditional smokeless tobacco products frequently appear to be moist and dirty. Moreover, American consumers generally react poorly to traditional smokeless tobacco products when they do try such products. It can be assumed that reactions may even be less favorable in countries which do not, like the U.S., have an incidence of modern smokeless use.
Snus style smokeless tobacco is a steam cured tobacco popularized in Norway and Sweden that is either loose or contained in a pouch and is placed in the cheek. Dipping tobacco, also known as American moist snuff or dip is also known. Now long cut tobacco has been put in single portion pouches in the past. Single portion pouches are considered convenient and are gaining increasing sales among smokeless tobacco users. Fine ground snuff tobacco has been known for centuries. Snuff is fine-ground tobacco intended for use by being sniffed or snorted into the nose or placed in the cheek. Regardless of whether tobacco is lose or in pouches, it is generally brown, often moist and is considered unsightly and unappealing by many smokers who are reluctant to use smokeless tobacco products. In addition, a certain social opprobrium is associated with tobacco-induced spitting and/or the removal of tobacco from the mouth after use.
As noted in a report by Swedish Match North Europe AB on its website at http://www.gothiatek.com/templates/start.aspx?page_id=73 entitled “Nicotine uptake from snus,” (the content, including the citations therein, of which is incorporated herein in its entirety), nicotine contained in Swedish snus, has well-documented pharmacological effects on the central nervous system. Both the dose and the uptake rate are of importance for understanding the biological effects of nicotine in humans. The amount of nicotine that is absorbed during snus use (nicotine dose) can be quantified by measuring the concentration of nicotine or its metabolites in different body fluids, i.e. blood, saliva and urine. The uptake rate can be estimated by monitoring the increase of the blood nicotine concentration over time. The nicotine uptake from Swedish snus has been described in six scientific publications of different objectives and design. As noted in that report, the nicotine uptake from one pinch of snus is determined both by the amount of nicotine that is released from the pinch during snus use and by the amount of nicotine that passes the buccal mucosa and reaches the systemic circulation; almost half of the nicotine present in the pinch was extracted during snus use (37% from portion-packed snus and 49% from loose snus). By comparison of the total amount of excreted nicotine with the total amount of nicotine in the pinch per time unit, it has been concluded that only 10-20% of the nicotine originally present in the snus pinch is absorbed via the buccal mucosa and reaches the systemic circulation. During snus use nicotine is absorbed via the oral mucosa.
Because smokeless tobacco users look to nicotine uptake as significant component to tobacco satisfaction, and it is desirable to improve the nicotine absorption from a given amount of tobacco, allowing the user to reduce the amount of tobacco used for a given level of nicotine absorption. However, no methods of enhanced nicotine absorption from amount of tobacco have been taught.
A pouch due to its thickness is exposed to a significant degree of saliva flow. This flow carries a percentage of nicotine which is significant down the throat and into the stomach, with the saliva. This nicotine is subject to first pass physiology as well. In addition the pouch wall also serves as an obstruction to nicotine outflow from the tobacco. Unpouched tobacco plugs and pinches are subject to the same dynamic.
The manufacture of reconstituted tobacco sheets is a known practice in the tobacco industry. A rich patent history documents the evolution of this art (see e.g. F. H. Wells et al U.S. Pat. No. 2,433,877, issued Jan. 6, 1948) (manufacture of a wet cast sheet to recapture tobacco scraps using cellulose as a binder)). The aim of such art has been to use small tobacco particles—waste product because the particles are too small to be used in cigarettes, cigars and the like—and to make a tobacco-like sheet which can be used as filler in a cigarette or as a cigar wrapper. The reconstituted tobacco sheet is intended to behave as tobacco itself, namely as an insoluble sheet to be smoked or used as a cigar wrapper.
A number of materials have been used as binders to help bind the tobacco particles together. These include HPC, HPMC, other celluloses, Pullulan, pectin, various gums etc. Perhaps most interestingly, the use of naturally occurring plant pectins as a binder is taught (see e.g. Hind et al U.S. Pat. No. 3,411,515, issued Nov. 19, 1968).
This use of naturally occurring pectins to re-form the tobacco leave in a reconstituted sheet explains the incredibly high concentrations of tobacco used relative to small amounts of binder to form such sheets. For example, Ehling et al U.S. Pat. No. 5,097,851, issued Mar. 24, 1992, discloses a tobacco sheet with just 1-8% binder and 86 to 98% by weight tobacco material. Such ratios are unheard of in the edible film industry and are indicative of tobacco's natural proclivity to re-form itself.
The basic methods of manufacture include wet casting and aqueous based extrusion. In wet casting, the tobacco is mixed with water and the binder. It is then cast—typically onto a steel belt—and the water content is substantially reduced during a drying stage. The reconstituted tobacco sheet is then removed from the belt. (See, e.g., Schmidt et al U.S. Pat. No. 4,144,894, issued Mar. 20, 1979.)
In aqueous based extrusion, tobacco particles are mixed with a binder and water is added. The water serves to hydrate the binder and activates its adhesives properties. This mixture is then run through an extruder and typically through a slot die (see e.g. Keritsis et al. U.S. Pat. No. 4,625,737, issued Dec. 2, 1986).
Water also serves to lower viscosity. High viscosity is a limitation of aqueous casting. Water is needed to deal with the high viscosities in cast film and in extruded sheets. Adding water to lower viscosity was an interim step as new inventive steps were required as are shown in this application.
Tobacco is a mature, efficient industry and this is reflected in the evolution of reconstituted tobacco sheet art over the past sixty years. The art has tended to move from wet casting towards extrusion—for reasons of output and cost. Removing moisture from a wet cast film requires substantial amounts of heat energy. The compositional art has become simpler and more tobacco like—more tobacco, less binder. The result is that such art provides little guidance for the development of the present invention. In its ultimate embodiment, reconstituted tobacco is a type of idealized tobacco (like nature's but with better mechanical properties, etc). Thus, reconstituted tobacco art would be useful if one where seeking to make a chewing tobacco like, insoluble product. But applicant has found that it is not helpful in connection with a sustained release dissolving tobacco sheet.
Edible films are typically made using a wet casting process. In discussing the existing art, applicant pointedly uses the term “film” and not sheet. This is because the inherent properties of the wet casting manufacturing process—as currently understood—do not allow for the manufacture of thicker sheets. Related to thickness, but directly corresponding is dissolution time. Also, wet cast edible films are typically quickly dissolving products, and practitioners have struggled—and not with great success—to extend the disintegration time of wet cast edible film products where a slower dissolving product would be more appropriate for the intended use.
The development of wet cast edible packaging films for various food and other applications commenced at least fifty years ago (see http://www.watson-inc.com/about_history.php). Other historical antecedents can be seen the wet cast manufacture of fruit pulps as well as rice based films in Asia.
Wet cast monolayer film compositions for pharmaceutical and vitamin delivery are disclosed in Fuchs et al. U.S. Pat. No. 4,136,162 issued Jan. 23, 1979. Schmidt discloses bilayer film compositions for pharmaceutical and food uses in U.S. Pat. No. 4,849,246 issued Jul. 18, 1989.
The inventor Horst Zerbe was issued U.S. Pat. No. 5,948,430 for film compositions for therapeutic agents and breath freshening agents. As Zerbe notes, the thickness of films should not exceed 2.7 mils so as to prevent adverse mouth feel. The assignee of this patent, Lohmann Therapeutic Systems (“LTS”), is credited with the manufacture of the first edible film to enjoy commercial success—namely, the 2001 commercial launch of pullulan based Listerine PocketPaks® Breath Strips (a product described more fully in Leung et al. 6596298 “Fast dissolving orally consumable films” and Leung et al. 6923981).
The Listerine PocketPaks® film is a very rapidly dissolving film. It dissolves in fewer than ten seconds and has a mass of just 33 mg. The product contains high moisture content and uses water to help impart the product with flexibility (a trait easily demonstrated by drying a Listerine strip—at which point it becomes very brittle and will crack and break when bent).
From breath freshening, wet cast film technology has moved to over-the-counter pharmaceutical products. The emphasis has still been on achieving rapid disintegration in the mouth. Noted thin film drug delivery company MonoSol Rx LLC describes its film technology on its website thusly: “MonoSol Rx has developed a thin film drug delivery technology that is more stable, durable and quicker dissolving than other conventional dosage forms. The thin film, which is similar in size, shape and thickness to a postage stamp, has the ability to carry very low doses of prescription products that are highly uniform, to larger doses up to 80 mg. The technology enables buckle and sublingual delivery [italics added].”
Other pharmaceutical thin film developers, such as LTS and Applied Pharma Research describe their film technologies in similar ways.
The transition of thin film drug delivery into pharmaceutical products required a new focus on meeting pharmaceutical criteria, like achieving and maintaining content uniformity of drug during the wet cast manufacturing process (see e.g. Yang et al. US 2003/0107149 A1). Wet cast compositional film art developed that could load increasing amounts of drug with continuing emphasis on quick disintegration of the film. (See Yang et al. US 2005/0037055 A1.)
One limitation of wet cast technology is the difficulty—indeed, the inability to wet cast films beyond a certain thickness range. This is due to the relationship between viscosity and coating thickness, which creates a practical limitation on the ability to coat beyond certain thickness levels, and the difficulty removing moisture from films past a certain thickness levels, even if they are successfully cast.
Limitations on thickness translate into limits on the amount of active ingredient a film can carry. The largest amount of solid active delivered by a commercially available film is 25 mg of diphenhydramine in Pfizer's Benadryl® strip. Likewise, limitations on thickness also limit the dissolution time of the film matrix. The challenge of extending dissolution times in monolayer wet cast media is evident in Fankhauser et al US 2007/0202057 A1, a case directed at cast films containing nicotine. This case uses bench scale formulation tricks including an ice water bath (to gel the polymer) to coax a monolayer wet cast film to a claimed fifteen minute disintegration time. That such a practice would involve immense challenges—arguably impossible—to scale to commercial manufacture is readily apparent.
Others have suggested the lamination of multiple films to slow the dissolution of the dosage form (see, e.g. LTS's website). This method is undoubtedly more practical from a manufacturing perspective than Fankhauser's proposed solution, but too costly to practice—even in the pharmaceutical space. As a result, such multiple film laminates are not seen in the marketplace as commercial products.
Even monolayer wet casting can be relatively expensive. Commercial equipment involves long drying ovens and is too heavy to be moved, requiring specialized production suites. Drying requires substantial volumes of filtered air, and substantial amounts of heat energy to remove moisture. These costs may be easily born by pharmaceutical products but can be challenging in the cost competitive global tobacco field.
Two additional points must be made—namely, the physical strength and physical stability of wet cast films. Wet cast films are typically cast on a substrate or backing paper. Among other things, the substrate lends physical strength to the film in processing until the film is delaminated from the substrate. If such films lack the requisite pliability and tensile strength, they will tend to break during packaging causing substantial losses in process yield. Such breakage issues presumably led to the filing of a patent on methods of film splicing (Slominski et al 20060207721). MonoSol Rx makes the most pliable, strong wet cast films, using their polyethelene oxide (PEO) based compositions (See Yang et al. US 2005/0037055 A1). The strength of these films as led to the subsequent use of PEO in formulations commercially sold by Novartis. The reality is that physical strength and resulting breakage and process yield issues have been significant problems for many of the non-PEO films.
The related issue of physical stability is also an issue for many wet cast films—expensive barrier packaging is often used as a matter of necessity. Still, physical stability is not always a given. Boots Chemists launched a Vitamin C strip manufactured by BioProgress in Tampa Fla. that had to be removed from the shelves because it was crumbling in the package—earning the name “chips not strips.” This story is not unique—many projects have failed to move out from development to commercialization due to physical stability issues.
In addition to issues with wet casting, the mixing of wet based compositions for casting itself raises certain challenges. First, the solvent itself adds volume to the mix. Wet compositions may tend to adhere to mixing vessels and any transit piping leading to yield losses. Foaming may be in issue. Wet mixtures must be de-gassed to avoid air bubbles which can reduce content uniformity. See, Fuisz et al. US 20080075825 A1.
Extruded edible products have a lengthy history—confections were being extruded in the 1920's (See P. B. Laskey U.S. Pat. No. 1,492,600). Extrusion has more recently been used in medical device manufacture and in the making of transdermal drug delivery systems—of course, these are both non-edible and insoluble. See, generally, Pharmaceutical Extrusion Technology, edited by Issac Ghebre-Sellassie and Charles Martin (2007), the content of which is incorporated herein in its entirety.
Inspired by the success of transdermal drug delivery systems, work began to extrude soluble, edible sheets and films for drug delivery use.
Schiraldi et al. (U.S. Pat. No. RE33,093) discloses bioadhesive monolayer extruded films, under 10 mils, composed of principally of polyethylene oxide together with a lesser amount of HPC, a water insoluble polymer, a plasticizer and a medicament. See also Mooney and Schiraldi, U.S. Pat. No. 6,072,100 disclosing compositions extruded fast dissolving films comprising a composition of PEO or HPC, a water polymer derived from a carboxylic aid, 30-80% plasticizer and up to 10% of a medicament.
Michael Repka and James McGinnity disclose hot melt extruded sheets with a thickness of 10-13 mils using a 50-50 ratio PEO and HPC, together with 3% of Vitamin E TPGS (see “Influence of Vitamin E TPGS on the properties of hydrophilic films produced by hot melt extrusion,” International Journal of Pharmaceutics 202 (2000) 63-70.
Repka et al U.S. Pat. No. 6,375,963 issued Apr. 23, 2002 disclose an extruded film composition that includes HPC, PEO, polycarbophil [an acrylic polymer] and the absence of a plasticizer.
A review of the Orange Book indicates that none of the above extrusion patents are used in an FDA approved pharmaceutical product nor are any such patents referenced on any over-the-counter product.
As the art demonstrates, practitioners have struggled to achieve required flexibility in hot melt extruded pharmaceutical films, and have relied on PEO, polycarbophil or extreme levels of plasticizer to achieve such flexibility of the sheet or film. Neither PEO nor polycarbophil is approved for food use outside of the US. Additionally, PEO is a very expensive polymer that is ill suited to tobacco products from a cost perspective. As a result, the pharmaceutical art on extruded films and sheets provides little guidance for the composition of the present invention.
Traditional tobacco products are removed from the mouth after use. These include chewing tobaccos, plugs, SNUS products and the like. Smokers are often reluctant to use these products because they are believed to be socially inappropriate since removal from the mouth can be embarrassing or can offend others.
Various dissolving tobacco products have been taught.
Williams U.S. Pat. No. 6,669,839, issued Dec. 30, 2003, discloses a low nitrosamine tobacco tablet comprising at least 50% tobacco.
Williams U.S. Pat. No. 6,834,654, issued Dec. 28, 2004, discloses a low nitrosamine tobacco composition formed from pulverized tobacco and consisting essentially of Virginia flue cured tobacco.
Pera U.S. Pat. No. 6,845,777, issued Jan. 25, 2005, discloses a product comprised of tobacco, an antioxidant, caffeine and S-Adenosyl-Methionine in a tablet or capsule that is allowed to disintegrate in the mouth or buccal cavity.
Strickland et al WO 2005/046363 discloses wet cast, fast dissolving HPMC based films containing tobacco (see Example B (wet cast HPMC based film of 2.5 mil thickness that disintegrates in less than one minute), Example D (two layer HPMC wt cast film—one layer with tobacco—that dissolves in less than one minute), Example E (three layer HPMC wet cast film that will disintegrate in less than one minute), Example F (an aerated wet cast HPMC film for even faster dissolution), Example K (an HPMC/starch wet cast film than disintegrates in less than one minute), Example L (an HPMC/starch wet cast film that disintegrated in 15-30 seconds) and Example M (an HPMC/starch wet cat film that disintegrated in 15-30 seconds). In Example R, a water based HPC based solution containing tobacco is fed through a twin-screw extruder at a rate of 1-3 pounds an hour, yielding a film of “thickness varying from 2-3 mils.” This film was apparently tacky—as one would expect from this composition and Mylar was placed “between the film layers to prevent adhesion.” Moisture levels of the finished product were not disclosed. Unlike the cast examples, it is noted this “tobacco film was placed in a container suitable for storage” presumably due to tackiness and other stability issues caused by exposure to ambient conditions. This film “disintegrated . . . over a period of 2-4 minutes.”
Wren WO 2007/138484 discloses fast dissolving film strips containing over 50% tobacco that dissolve in less than a minute and “preferably faster.” Wren mentions pullulan, cellulose ethers, sodium alginate, pectin, gums and mixtures thereof as “binders”. Wren discloses a wet casting manufacturing process.
Mua et al US 2008/0029117 A1 disclose examples of wet cast films containing tobacco, and aqueous mixtures that are extruded as films or sheets through a pasta maker. The examples are primarily alginate based but may also include HPMC, HPC and starches.
The quick dissolving tobacco strips that are disclosed in the above art are basic film compositions that disintegrate rapidly in the mouth. It is highly doubtful that such fast dissolving products could deliver acceptable tobacco satisfaction, including sufficient nicotine absorption. Instead, the matrix will fully dissolve before acceptable nicotine is absorbed from the tobacco, and the tobacco from the dissolved matrix will be swallowed. Undoubtedly, this is part of the reason why none of these products have been sold commercially.
While there is constructive mention of “extrusion” and some extruded water based films, hot melt extrusion of sheets and/or films containing tobacco is not taught either in method or composition. As is seen the pharmaceutical art concerning hot melt extrusion of sheets and/or films containing active ingredients involves real challenges which must be overcome, as they are by the present invention.
Thus, it is still desirable to provide a more efficient way to absorb nicotine from tobacco.